1. Field of the Invention
The present invention relates to (i) 6-amino-2,2-dimethyl-3,4,6-trisubstituted benzopyran derivatives; (ii) a process for synthesizing the novel benzopyran derivatives with high efficiency by parallel synthesis on solid-phase as one of combinatorial chemical synthesis technologies; and (iii) a use of the novel benzopyran derivatives for preventing and treating diseases or disorders induced by promotion of lipid peroxidation or accumulation of oxidized products.
2. Description of the Related Art
It has been suggested that the injury or death (e.g., apoptosis) of nerve cells is mainly responsible for several neurologic diseases or disorders such as apoplexy, brain trauma, Alzheimer's disease and Parkinson's disease (G. J. Zoppo et al., Drugs 54, 9 (1997); and I. Sziraki et al., Neurosci. 85, 1101 (1998)). The factors involved in the injury of nerve cells have been known, which include the elevation of the levels of iron, activated oxygen species and oxidized molecules in nerve cells (M. P. Mattson et al., Methods Cell Biol. 46, 187 (1995); and Y. Goodman et al., Brain Res. 706, 328 (1996)).
The elevated level of iron in nerve cells leads to the formation of oxygen free radicals such as NO and then promotion of lipid peroxidation, which results in the accumulation of oxidized molecules in cells. The oxidized molecules accumulated in cells give rise to inflammatory diseases, cardiac infarction and dementia as well as neurologic diseases described above. In addition, the oxidized molecules have been reported to lead to acute or chronic tissue or organ injury. Such injuries include organ injury by endotoxins from bacteria infection or tissue injury occurring when the reperfusion in ischemic disease is performed.
Therefore, in order to prevent and treat several diseases due to the injury or death of nerve cells, many researchers have made extensive study to develop novel substances capable of preventing injury of nerve cells due to elevated irons in nerve cells, lipid peroxidation and generation of NO due to endotoxins. The antioxidants have been reported to alleviate injury and death of nerve cells due to irons, and the endeavor to develop novel drugs for preventing injury of nerve cells due to oxidative stress is under way (Y. Zhang et al., J. Cereb. Blood Flow Metab. 13, 378 (1993)).
Natural and synthetic products having benzopyran skeleton have been widely known and used as a basic skeletal structure for developing compounds exhibiting therapeutical efficacy in several diseases such as nerve-related diseases, hypertension and diabetes owing to their antioxidation activity.
Construction of benzopyran library having a wide variety of derivatives by means of the technology of combinatorial chemical synthesis is very useful in exploiting hit or lead compounds at the initial stage for developing new drugs.
In particular, it is very important that the library of small organic molecular compounds, wherein various substituents can be introduced and Lipinsky's Rule of 5 can be largely applied, is constructed in a massive and effective manner, in view of the strategy for obtaining molecular diversity useful in screening lead compounds.
The combinatorial chemical synthesis has been focused as a new technology for developing novel substances. Compared to conventional methods where a single compound is synthesized by a single reaction, the technology of combinatorial chemical synthesis allows to synthesize more diverse and abundant compounds simultaneously and to automate a multi-step synthesis, so that it is considered as a highly effective process of synthesizing compounds. The introduction of combinatorial chemical synthesis makes it easier to screen and optimize biological hit and lead compounds having novel structures.
Since the technology of combinatorial chemical synthesis is generally carried out on a solid support, a continuous multi-step process can be automated. In addition, because the isolation and purification of products in this technology is very simple, the high throughput screening for pharmacological efficacy is also made possible.
Although the approach of the combinatorial chemical synthesis appears to overcome the shortcomings of conventional synthesis methods as being uneconomical and ineffective, several bottlenecks still prevents it from being applied to the field of organic synthesis. One such reason is that undesired side reactions occur because most of chemical reactions on a solid support employ excess reagents. Another reason is that the selection of reaction conditions is very restricted because solvents that can be used depend on physical properties of a solid support. In the art of combinatorial chemical synthesis on a solid support, Merrifield resin and Wang resin have been often used as a solid support. However, these supports show negligible swelling effect in a high polar solvent such as alcohol and water, thereby restricting the selection of a solvent for a reaction. Therefore, in order to synthesize diverse derivatives by use of chemical reactions on a solid support, the selection of a solid support and a reaction reagent as well as the screening of reaction conditions become essential.